The genetic control of puberty remains an important but mostly unanswered question. Late pubertal timing affects over 2% of adolescents and is associated with adverse health outcomes including short stature, reduced bone mineral density, and compromised psychosocial health. Self-limited delayed puberty (DP) is a highly heritable trait, which often segregates in an autosomal dominant pattern; however, its neuroendocrine pathophysiology and genetic regulation remain unclear. Some insights into the genetic mutations that lead to familial DP have come from sequencing genes known to cause gonadotropin-releasing hormone (GnRH) deficiency, most recently via next-generation sequencing, and others from large-scale genome-wide association studies in the general population. Investigation of the genetic control of DP is complicated by the fact that this trait is not rare and that the phenotype is likely to represent a final common pathway, with a variety of different pathogenic mechanisms affecting the release of the puberty “brake.” These include abnormalities of GnRH neuronal development and function, GnRH receptor and luteinizing hormone/follicle-stimulating hormone abnormalities, metabolic and energy homeostatic derangements, and transcriptional regulation of the hypothalamic-pituitary-gonadal axis. Thus, genetic control of pubertal timing can range from early fetal life via development of the GnRH network to those factors directly influencing the puberty brake during mid-childhood.

Keywords:
Pubertal timing, Self-limited delayed puberty, Constitutional delay, Genetics, Adolescent development
1.
Cariboni A, Maggi R, Parnavelas JG: From nose to fertility: the long migratory journey of gonadotropin-releasing hormone neurons. Trends Neurosci 2007;30:638-644.
2.
Karges B, Neulen J, de Roux N, Karges W: Genetics of isolated hypogonadotropic hypogonadism: role of GnRH receptor and other genes. Int J Endocrinol 2012;2012:147893.
3.
de Muinich Keizer SM, Mul D: Trends in pubertal development in Europe. Hum Reprod Update 2001;7:287-291.
4.
Wehkalampi K, Widén E, Laine T, Palotie A, Dunkel L: Patterns of inheritance of constitutional delay of growth and puberty in families of adolescent girls and boys referred to specialist pediatric care. J Clin Endocrinol Metab 2008;93:723-728.
5.
Gajdos ZK, Hirschhorn JN, Palmert MR: What controls the timing of puberty? An update on progress from genetic investigation. Curr Opin Endocrinol Diabetes Obes 2009;16:16-24.
6.
Parent AS, Teilmann G, Juul A, Skakkebaek NE, Toppari J, Bourguignon JP: The timing of normal puberty and the age limits of sexual precocity: variations around the world, secular trends, and changes after migration. Endocr Rev 2003;24:668-693.
7.
Palmert MR, Dunkel L: Clinical practice. Delayed puberty. N Engl J Med 2012;366:443-453.
8.
Lawaetz JG, Hagen CP, Mieritz MG, Blomberg Jensen M, Petersen JH, Juul A: Evaluation of 451 Danish boys with delayed puberty: diagnostic use of a new puberty nomogram and effects of oral testosterone therapy. J Clin Endocrinol Metab 2015;100:1376-1385.
9.
Zhu J, Chan YM: Adult consequences of self-limited delayed puberty. Pediatrics 2017;139:e20163177.
10.
Sedlmeyer IL, Palmert MR: Delayed puberty: analysis of a large case series from an academic center. J Clin Endocrinol Metab 2002;87:1613-1620.
11.
Sedlmeyer IL, Hirschhorn JN, Palmert MR: Pedigree analysis of constitutional delay of growth and maturation: determination of familial aggregation and inheritance patterns. J Clin Endocrinol Metab 2002;87:5581-5586.
12.
Ong KK, Elks CE, Li S, Zhao JH, Luan J, Andersen LB, et al: Genetic variation in LIN28B is associated with the timing of puberty. Nat Genet 2009;41:729-733.
13.
Perry JR, Day F, Elks CE, Sulem P, Thompson DJ, Ferreira T, et al: Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche. Nature 2014;514:92-97.
14.
Elks CE, Perry JR, Sulem P, Chasman DI, Franceschini N, He C, et al: Thirty new loci for age at menarche identified by a meta-analysis of genome-wide association studies. Nat Genet 2010;42:1077-1085.
15.
Perry JR, Stolk L, Franceschini N, Lunetta KL, Zhai G, McArdle PF, et al: Meta-analysis of genome-wide association data identifies two loci influencing age at menarche. Nat Genet 2009;41:648-650.
16.
Tommiska J, Wehkalampi K, Vaaralahti K, Laitinen EM, Raivio T, Dunkel L: LIN28B in constitutional delay of growth and puberty. J Clin Endocrinol Metab 2010;95:3063-3066.
17.
Silveira-Neto AP, Leal LF, Emerman AB, Henderson KD, Piskounova E, Henderson BE, et al: Absence of functional LIN28B mutations in a large cohort of patients with idiopathic central precocious puberty. Horm Res Paediatr 2012;78:144-150.
18.
Day FR, Thompson DJ, Helgason H, Chasman DI, Finucane H, Sulem P, et al: Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk. Nat Genet 2017;49:834-841.
19.
Abreu AP, Dauber A, Macedo DB, Noel SD, Brito VN, Gill JC, et al: Central precocious puberty caused by mutations in the imprinted gene MKRN3. N Engl J Med 2013;368:2467-2475.
20.
Dauber A, Cunha-Silva M, Macedo DB, Brito VN, Abreu AP, Roberts SA, et al: Paternally inherited DLK1 deletion associated with familial central precocious puberty. J Clin Endocrinol Metab 2017;102:1557-1567.
21.
Silveira LG, Noel SD, Silveira-Neto AP, Abreu AP, Brito VN, Santos MG, et al: Mutations of the KISS1 gene in disorders of puberty. J Clin Endocrinol Metab 2010;95:2276-2280.
22.
Teles MG, Bianco SD, Brito VN, Trarbach EB, Kuohung W, Xu S, et al: A GPR54-activating mutation in a patient with central precocious puberty. N Engl J Med 2008;358:709-715.
23.
Raivio T, Falardeau J, Dwyer A, Quinton R, Hayes FJ, Hughes VA, et al: Reversal of idiopathic hypogonadotropic hypogonadism. N Engl J Med 2007;357:863-873.
24.
Pitteloud N, Quinton R, Pearce S, Raivio T, Acierno J, Dwyer A, et al: Digenic mutations account for variable phenotypes in idiopathic hypogonadotropic hypogonadism. J Clin Invest 2007;117:457-463.
25.
Chevrier L, Guimiot F, de Roux N: GnRH receptor mutations in isolated gonadotropic deficiency. Mol Cell Endocrinol 2011;346: 21-28.
26.
Lin L, Conway GS, Hill NR, Dattani MT, Hindmarsh PC, Achermann JC: A homozygous R262Q mutation in the gonadotropin-releasing hormone receptor presenting as constitutional delay of growth and puberty with subsequent borderline oligospermia. J Clin Endocrinol Metab 2006;91:5117-5121.
27.
Vaaralahti K, Wehkalampi K, Tommiska J, Laitinen EM, Dunkel L, Raivio T: The role of gene defects underlying isolated hypogonadotropic hypogonadism in patients with constitutional delay of growth and puberty. Fertil Steril 2011;95:2756-2758.
28.
Pugliese-Pires PN, Fortin JP, Arthur T, Latronico AC, Mendonca BB, Villares SM, et al: Novel inactivating mutations in the GH secretagogue receptor gene in patients with constitutional delay of growth and puberty. Eur J Endocrinol 2011;165:233-241.
29.
Tornberg J, Sykiotis GP, Keefe K, Plummer L, Hoang X, Hall JE, et al: Heparan sulfate 6-O-sulfotransferase 1, a gene involved in extracellular sugar modifications, is mutated in patients with idiopathic hypogonadotrophic hypogonadism. Proc Natl Acad Sci USA 2011;108:11524-11529.
30.
Pitteloud N, Meysing A, Quinton R, Acierno JS Jr, Dwyer AA, Plummer L, et al: Mutations in fibroblast growth factor receptor 1 cause Kallmann syndrome with a wide spectrum of reproductive phenotypes. Mol Cell Endocrinol 2006;254-255:60-69.
31.
Xu C, Messina A, Somm E, Miraoui H, Kinnunen T, Acierno JS Jr, et al: KLB, encoding β-Klotho, is mutated in patients with congenital hypogonadotropic hypogonadism. EMBO Mol Med 2017;9:1379-1397.
32.
Zhu J, Choa RE, Guo MH, Plummer L, Buck C, Palmert MR, et al: A shared genetic basis for self-limited delayed puberty and idiopathic hypogonadotropic hypogonadism. J Clin Endocrinol Metab 2015;100:E646-E654.
33.
Kelberman D, Rizzoti K, Lovell-Badge R, Robinson IC, Dattani MT: Genetic regulation of pituitary gland development in human and mouse. Endocr Rev 2009;30:790-829.
34.
Parks JS, Brown MR, Hurley DL, Phelps CJ, Wajnrajch MP: Heritable disorders of pituitary development. J Clin Endocrinol Metab 1999;84:4362-4370.
35.
Achermann JC, Gu WX, Kotlar TJ, Meeks JJ, Sabacan LP, Seminara SB, et al: Mutational analysis of DAX1 in patients with hypogonadotropic hypogonadism or pubertal delay. J Clin Endocrinol Metab 1999;84:4497-4500.
36.
Wolf NI, Vanderver A, van Spaendonk RM, Schiffmann R, Brais B, Bugiani M, et al; 4H Research Group: Clinical spectrum of 4H leukodystrophy caused by POLR3A and POLR3B mutations. Neurology 2014;83:1898-1905.
37.
Margolin DH, Kousi M, Chan YM, Lim ET, Schmahmann JD, Hadjivassiliou M, et al: Ataxia, dementia, and hypogonadotropism caused by disordered ubiquitination. N Engl J Med 2013;368:1992-2003.
38.
Topaloglu AK, Lomniczi A, Kretzschmar D, Dissen GA, Kotan LD, McArdle CA, et al: Loss-of-function mutations in PNPLA6 encoding neuropathy target esterase underlie pubertal failure and neurological deficits in Gordon Holmes syndrome. J Clin Endocrinol Metab 2014;99:E2067-E2075.
39.
Tata B, Huijbregts L, Jacquier S, Csaba Z, Genin E, Meyer V, et al: Haploinsufficiency of Dmxl2, encoding a synaptic protein, causes infertility associated with a loss of GnRH neurons in mouse. PLoS Biol 2014;12:e1001952.
40.
Aligianis IA, Johnson CA, Gissen P, Chen D, Hampshire D, Hoffmann K, et al: Mutations of the catalytic subunit of RAB3GAP cause Warburg Micro syndrome. Nat Genet 2005;37:221-223.
41.
Bem D, Yoshimura S, Nunes-Bastos R, Bond FC, Kurian MA, Rahman F, et al: Loss-of-function mutations in RAB18 cause Warburg Micro syndrome. Am J Hum Genet 2011;88:499-507.
42.
Themmen APN, Huhtaniemi IT: Mutations of gonadotropins and gonadotropin receptors: elucidating the physiology and pathophysiology of pituitary-gonadal function. Endocr Rev 2000;21:551-583.
43.
Layman LC, Lee EJ, Peak DB, Namnoum AB, Vu KV, van Lingen BL, et al: Delayed puberty and hypogonadism caused by mutations in the follicle-stimulating hormone β-subunit gene. N Engl J Med 1997;337:607-611.
44.
de Roux N, Genin E, Carel JC, Matsuda F, Chaussain JL, Milgrom E: Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54. Proc Natl Acad Sci USA 2003;100:10972-10976.
45.
Seminara SB, Messager S, Chatzidaki EE, Thresher RR, Acierno JS Jr, Shagoury JK, et al: The GPR54 gene as a regulator of puberty. N Engl J Med 2003;349:1614-1627.
46.
Topaloglu AK, Tello JA, Kotan LD, Ozbek MN, Yilmaz MB, Erdogan S, et al: Inactivating KISS1 mutation and hypogonadotropic hypogonadism. N Engl J Med 2012;366:629-635.
47.
Topaloglu AK, Reimann F, Guclu M, Yalin AS, Kotan LD, Porter KM, et al: TAC3 and TACR3 mutations in familial hypogonadotropic hypogonadism reveal a key role for Neurokinin B in the central control of reproduction. Nat Genet 2009;41:354-358.
48.
de Croft S, Boehm U, Herbison AE: Neurokinin B activates arcuate kisspeptin neurons through multiple tachykinin receptors in the male mouse. Endocrinology 2013;154:2750-2760.
49.
Rance NE: Menopause and the human hypothalamus: evidence for the role of kisspeptin/neurokinin B neurons in the regulation of estrogen negative feedback. Peptides 2009;30:111-122.
50.
Dungan HM, Clifton DK, Steiner RA: Minireview: kisspeptin neurons as central processors in the regulation of gonadotropin-releasing hormone secretion. Endocrinology 2006;147:1154-1158.
51.
Sandoval-Guzmán T, Rance NE: Central injection of senktide, an NK3 receptor agonist, or neuropeptide Y inhibits LH secretion and induces different patterns of Fos expression in the rat hypothalamus. Brain Res 2004;1026:307-312.
52.
Kung TT, Crawley Y, Jones H, Luo B, Gilchrest H, Greenfeder S, et al: Tachykinin NK3-receptor deficiency does not inhibit pulmonary eosinophilia in allergic mice. Pharmacol Res 2004;50:611-615.
53.
Tusset C, Noel SD, Trarbach EB, Silveira LF, Jorge AA, Brito VN, et al: Mutational analysis of TAC3 and TACR3 genes in patients with idiopathic central pubertal disorders. Arq Bras Endocrinol Metabol 2012;56:646-652.
54.
Mitsushima D, Hei DL, Terasawa E: γ- Aminobutyric acid is an inhibitory neurotransmitter restricting the release of luteinizing hormone-releasing hormone before the onset of puberty. Proc Natl Acad Sci USA 1994;91:395-399.
55.
Ojeda SR, Lomniczi A, Mastronardi C, Heger S, Roth C, Parent AS, et al: Minireview: the neuroendocrine regulation of puberty: is the time ripe for a systems biology approach? Endocrinology 2006;147:1166-1174.
56.
Ducret E, Anderson GM, Herbison AE: RFamide-related peptide-3, a mammalian gonadotropin-inhibitory hormone ortholog, regulates gonadotropin-releasing hormone neuron firing in the mouse. Endocrinology 2009;150:2799-2804.
57.
Ojeda SR, Lomniczi A, Sandau US: Glial- gonadotrophin hormone (GnRH) neurone interactions in the median eminence and the control of GnRH secretion. J Neuroendocrinol 2008;20:732-742.
58.
Ojeda SR, Dubay C, Lomniczi A, Kaidar G, Matagne V, Sandau US, Dissen GA: Gene networks and the neuroendocrine regulation of puberty. Mol Cell Endocrinol 2010;324:3-11.
59.
Ojeda SR, Hill J, Hill DF, Costa ME, Tapia V, Cornea A, Ma YJ: The Oct-2 POU domain gene in the neuroendocrine brain: a transcriptional regulator of mammalian puberty. Endocrinology 1999;140:3774-3789.
60.
Lee BJ, Cho GJ, Norgren RB Jr, Junier MP, Hill DF, Tapia V, et al: TTF-1, a homeodomain gene required for diencephalic morphogenesis, is postnatally expressed in the neuroendocrine brain in a developmentally regulated and cell-specific fashion. Mol Cell Neurosci 2001;17:107-126.
61.
Heger S, Mastronardi C, Dissen GA, Lomniczi A, Cabrera R, Roth CL, et al: Enhanced at puberty 1 (EAP1) is a new transcriptional regulator of the female neuroendocrine reproductive axis. J Clin Invest 2007;117:2145-2154.
62.
Messina A, Langlet F, Chachlaki K, Roa J, Rasika S, Jouy N, et al: A microRNA switch regulates the rise in hypothalamic GnRH production before puberty. Nat Neurosci 2016;19:835-844.
63.
Parent AS, Franssen D, Fudvoye J, Gérard A, Bourguignon JP: Developmental variations in environmental influences including endocrine disruptors on pubertal timing and neuroendocrine control: revision of human observations and mechanistic insight from rodents. Front Neuroendocrinol 2015;38:12-36.
64.
Ong KK, Ahmed ML, Dunger DB: Lessons from large population studies on timing and tempo of puberty (secular trends and relation to body size): the European trend. Mol Cell Endocrinol 2006;254-255:8-12.
65.
Biro FM, Khoury P, Morrison JA: Influence of obesity on timing of puberty. Int J Androl 2006;29:272-277; discussion 286-290.
66.
Frisch RE, McArthur JW: Menstrual cycles: fatness as a determinant of minimum weight for height necessary for their maintenance or onset. Science 1974;185:949-951.
67.
Elias CF: Leptin action in pubertal development: recent advances and unanswered questions. Trends Endocrinol Metab 2012;23:9-15.
68.
Barash IA, Cheung CC, Weigle DS, Ren H, Kabigting EB, Kuijper JL, et al: Leptin is a metabolic signal to the reproductive system. Endocrinology 1996;137:3144-3147.
69.
Gill MS, Hall CM, Tillmann V, Clayton PE: Constitutional delay in growth and puberty (CDGP) is associated with hypoleptinaemia. Clin Endocrinol (Oxf) 1999;50:721-726.
70.
Banerjee I, Trueman JA, Hall CM, Price DA, Patel L, Whatmore AJ, et al: Phenotypic variation in constitutional delay of growth and puberty: relationship to specific leptin and leptin receptor gene polymorphisms. Eur J Endocrinol 2006;155:121-126.
71.
Pomerants T, Tillmann V, Karelson K, Jürimäe J, Jürimäe T: Ghrelin response to acute aerobic exercise in boys at different stages of puberty. Horm Metab Res 2006;38:752-757.
72.
Persson I, Ahlsson F, Ewald U, Tuvemo T, Qingyuan M, von Rosen D, Proos L: Influence of perinatal factors on the onset of puberty in boys and girls: implications for interpretation of link with risk of long term diseases. Am J Epidemiol 1999;150:747-755.
73.
Wehkalampi K, Hovi P, Dunkel L, Strang-Karlsson S, Järvenpää AL, Eriksson JG, et al: Advanced pubertal growth spurt in subjects born preterm: the Helsinki Study of Very Low Birth Weight Adults. J Clin Endocrinol Metab 2011;96:525-533.
74.
Dunger DB, Ahmed ML, Ong KK: Early and late weight gain and the timing of puberty. Mol Cell Endocrinol 2006;254-255:140-145.
75.
Sun Y, Bak B, Schoenmakers N, van Trotsenburg AS, Oostdijk W, Voshol P, et al: Loss-of-function mutations in IGSF1 cause an X-linked syndrome of central hypothyroidism and testicular enlargement. Nat Genet 2012;44:1375-1381.
76.
Joustra SD, Wehkalampi K, Oostdijk W, Biermasz NR, Howard S, Silander TL, et al: IGSF1 variants in boys with familial delayed puberty. Eur J Pediatr 2015;174:687-692.
77.
Howard SR, Guasti L, Ruiz-Babot G, Mancini A, David A, Storr HL, et al: IGSF10 mutations dysregulate gonadotropin-releasing hormone neuronal migration resulting in delayed puberty. EMBO Mol Med 2016;8:626-642.
78.
Boehm U, Bouloux PM, Dattani MT, de Roux N, Dodé C, Dunkel L, et al: Expert consensus document: European Consensus Statement on congenital hypogonadotropic hypogonadism - pathogenesis, diagnosis and treatment. Nat Rev Endocrinol 2015;11:547-564.
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